Piperazine derivatives



United States Patent-O PIPERAZINE DERIVATIVES Raymond J. Michaels, Jr., Mundelein, and Harold E.

Zaugg, Lake Forest, 111., assignors to 'Abbott Laboratories, North Chicago, 111., a corporation of Illinois D i Application September 25, 1957 j ..f

' Serial No. 686,015

4 Claims. c1. 2 0. 268

This invention relates to a new series of carbinol amines, in particular, amines-comprising substituted N-heterocyclic rings and to novel methods. of. preparing same. The compounds'of this invention are represented by the following structural formula:

where R and R are hydrogen orloweralkyl and Y is pyridine, hydrogen, loweralkyl hydroxy and loweralkyl.

Examples of compounds substituted at the N position are N-Z-pyridylpiperazine, N-p-hydroxyethyl-piperazine and the like. position are represented by Z-methylpiperazine and the like, and loweralkyl piperazines disubstituted at various carbon positions are represented, for example, by 2,5- dimethyl-piperazine and the like.

The compounds are prepared by reacting 1,1 -diphenylethylene oxide with the secondary amino group comprising a portion of the selected N-heterocyclic ring. In this manner, the said amino group participates in the reaction with 1,1-diphenylethylene oxide to give the substituted N-heterocyclic derivatives of fl-substituted derivatives of a,a-diphenylethanol.

Salts of the foregoing compounds are prepared and are intended to comprise a part of this invention. By the term salts, it is intended that they include acid additions salts of said compounds as well as the quaternary ammonium salts formed at the tertiary. nitrogen.

The compounds of this invention have been found to Monosubstituted piperazines" at a carbon? Patented Feb. 16, 1960 8 ice N'-2. pyridylpipera zine is precipitated in a yield of 1.9 53% M.P. 123-4 c-. .elnalysis..-Cal cd. for C H N O: ,'C, 76.85%; H, 7.01%;N, 11.69%; 0, 4.45%. Found: C, 76.59%; H, 7-.11 %;N,11.72%;O,4.23%. C EXAMPLE 11 piperazine:

;}1',-1-diphenylethylene oxide 2.9 gms., .ois mole) is combined with1N- S-hydroxylethylpiperazine (3.9 gms.,

.03 mole) and the reaction is conducted according to "The MP. of the trihydrochloride salt of the above named amine is 2478 C. and it is collected in a yield of 2.2 gins.

Anal sis-cact for C H N O-3HCl: c, 56.19%; H, 7.19%; N, 9.36%. Found: C, 56.26%; N,-9.28%.

EXAMPLE IV 8 1,1diphenylethylene oxide (2.9 gms., .015 mole) is added portionwise to 2,5-dimethylpiperazine (14 gms.,

.07 mole) and the reaction is conducted according to the procedure of Example I.

The M.P. of the dihydrochloride salt of the above v named amine is 335-6" C. and itis collected in a yield of 7.9 gms.

show anti-spasmodic activity and antiarkinson activity.

The following examples are, intended to serve as an illustration of the workings of this'invention and. are not intended to limit the products and steps to the exact ingredients and proportions stated therein. p i

. EXAMPLE I N-(flfi-diphenyl-p-hydroxethyl) -N-2-pyridylpiperazine V 1,1-diphenylethylene oxide (2.0 gms., .01 mole) is. combined with N-(2-pyridyl)-piperazine (3.3 gms.,, .02 mole) and the resulting mixture is heated for 16 hours on the steam bath. About 50 cc. of water is added-to.

the cooled reaction mixture to precipitate the crude oily product. The product is extracted with ether and the extract is dried over anhydrous sodium sulfate. The drying agent is removed by filtration and the ether is evaporated to isolate the product, N-(fl,B-diphenyl-flhydroxyethyl)-N-2-pyridylpiperazine., The product is V taken up in 30 cc. of isopropyl alcohol and excess isopfropyl alcoholic hydrogen, chloride, from which the diydrochloride salt of N-(p,fi-diphenyl-p-hydroxyethyl)- 61.22%; N, 7.45%; H, 7.14%. Found: C, 61.07%; H, 7.42%; N, 7.35%.

- EXAMPLE V 2,6-dimethyl-4-(fl,fi-diphenyl-p-hydroxyethyl) piperazine Lbdiphenylethylene oxide (2.9 gms., .015 mole) is added portionwise to 2,6-dimethylpiperazine (14 gms., .07 mole) and the reaction is conducted according to the procedure of Example I.

The M.P. of the base is 72-3 C. and it is collected in the'yield of 9.0 gms. (41% ,Analysis.-Calcd. for c,,H,-,N,o= c, 77.38%; H, I,

8.44%; N, 7.02%. Found: C, 77.53%; H, 8.47%; N,

p 7 EXAMPLE VI 7 2- methyl-4 (B,fi -diphenyl-p-lzydroxyethyl) .piperazine 1,1-diphenylethylene' oxide (14 gms,, .07 'mole) is added portionwise to 2-methylpiperazine (21 gms., .21 mole) and the reaction is conducted according to the procedure of Example I.

. Thecollected base 1s chloride to form the dihydrochloride salt of 2-methyl-4- ('5,fl-diphenyl-p-hydroxyethyl) piperazine and it is collected in a yield of 13.3 gms. (51%), M.P. 223-5 C.

. Ahalysis.-Calcdfor C H N O-2HCl: .C, 61.78%; I -H, 7.10%; N, 7.59%. Found: C,'61.67%; H, 7.21%;

1-methy1-4-(p-aminoethyl) -piperazine treated with alcoholic hydrogen 6 EXAMPLE VII 1,2-dimethyl-4-(fi,13-diphenyl-B-hydroxyez'hyl) piperazine The base of Example VI, 2-methyl-4-(fifi-diphenyl-flhydroxyethyl) piperazine, is treated with 1.2 gms. (.02 mole) of a formic acid solution (90%) and 1.4 gins. of 2. formaldehyde solution (35%). This methylation step results in the production of the base, 1,2-dimethyl- 4-(B,fldiphenyl-fi-hydroxyethyl) piperazine. Subsequent treatment with alcoholic hydrogen chloride results in the dihydrochlon'de salt of said base in a yield of 3.9 gms. (72%), MP. 170-172 C.

Analysis.Calcd. for C H N O-2HCl: C, 62.66%; H, 7.36%; N, 7.31%. Found: C, 62.55%; H, 7.38%; N, 7.33%.

Others may practice the invention in any of the numerous ways which will be suggestedby this disclosure to one skilled in the-art. All such practice of the invention is considered to be a part hereof provided it falls within the scope of the appended claims.

We claim:

1. N- (13,5 diphenyl fl hydroxyethyl) N 2- pyridylpiperazine.

References Cited in the file of this patent UNITEDSTATES PATENTS 2,633,467 De Benneville Mar. 31, 1953 2,706,194 Morris et al Apr. 12, 1955 FOREIGN PATENTS 683,950 Great Britain Dec. 10, 1952 OTHER REFERENCES Beck 'et '21.: Join. Amer. Chem. Soc., vol. 74, pp.

Chemical Abstracts, vol. 25, p.'5170 (1931). 

1. N - (B,B - DIPHENYL- B - HYDROXYETHYL) - N'' - 2PYRIDYLPIPERAZINE. 